The interleukin-2 receptor alpha chain (also called Tac antigen, P55, and mainly CD25) is a protein involved in the assembly of the high-affinity

interleukin-2 receptor The interleukin-2 receptor (IL-2R) is a heterotrimeric protein expressed on the surface of certain immune cells, such as lymphocytes, that binds and responds to a cytokine called IL-2. Composition IL-2 binds to the IL-2 receptor, which has ...

, consisting of alpha (''IL2RA''), beta ('' IL2RB'') and the common gamma chain (''

IL2RG The common gamma chain (γc) (or CD132), also known as interleukin-2 receptor subunit gamma or IL-2RG, is a cytokine receptor sub-unit that is common to the receptor complexes for at least six different interleukin receptors: IL-2, IL-4, IL-7 ...

''). As the name indicates, this receptor interacts with

interleukin-2 Interleukin-2 (IL-2) is an interleukin, which is a type of cytokine signaling molecule forming part of the immune system. It is a 15.5–16 kDa protein that regulates the activities of white blood cells (leukocytes, often lymphocytes) ...

, a pleiotropic

cytokine Cytokines () are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are produced by a broad range of cells, including immune cells like macrophages, B cell, B lymphocytes, T cell, T lymphocytes ...

which plays an important role in immune

homeostasis In biology, homeostasis (British English, British also homoeostasis; ) is the state of steady internal physics, physical and chemistry, chemical conditions maintained by organism, living systems. This is the condition of optimal functioning fo ...

Genetics

The human

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

interleukin-2 receptor subunit alpha is encoded by a

gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

called ''IL2RA'' with a length around 51,6 kb. Alternative names for this protein coding gene are ''IL2R'', ''IDDM10'' and ''TCGFR''. Location of ''IL2RA'' in human

genome A genome is all the genetic information of an organism. It consists of nucleotide sequences of DNA (or RNA in RNA viruses). The nuclear genome includes protein-coding genes and non-coding genes, other functional regions of the genome such as ...

is on the short arm of 10th chromosome (10p15.1). Several frequent point

mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, ...

single nucleotide polymorphism In genetics and bioinformatics, a single-nucleotide polymorphism (SNP ; plural SNPs ) is a germline substitution of a single nucleotide at a specific position in the genome. Although certain definitions require the substitution to be present in ...

(SNP), have been identified in or in close proximity to ''IL2RA'' gene in the population. These SNPs have been linked mainly to susceptibility to immune dysregulation disorders, with majority found in research on

multiple sclerosis Multiple sclerosis (MS) is an autoimmune disease resulting in damage to myelinthe insulating covers of nerve cellsin the brain and spinal cord. As a demyelinating disease, MS disrupts the nervous system's ability to Action potential, transmit ...

(MS) and type 1 diabetes mellitus. ''IL2RA'' gene orthologues with identical protein functionality are relatively abundant and constant among animal species, especially in

mammal A mammal () is a vertebrate animal of the Class (biology), class Mammalia (). Mammals are characterised by the presence of milk-producing mammary glands for feeding their young, a broad neocortex region of the brain, fur or hair, and three ...

s subgroups. Moreover, conserved homologs of this gene are in mouse, rat, dog, cow, chimpanzee and Rhesus monkey.

Expression

CD25 is expressed broadly among

leukocytes White blood cells (scientific name leukocytes), also called immune cells or immunocytes, are cells of the immune system that are involved in protecting the body against both infectious disease and foreign entities. White blood cells are genera ...

. The highest surface expression of this protein is on regulatory T cells (Tregs), where CD25 is expressed constitutively, especially on a subset classified as naturally occurring Tregs. It can also be found on activated

B cells B cells, also known as B lymphocytes, are a type of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system. B cells produce antibody molecules which may be either secreted or inserted into the plasm ...

, NK (natural killer) cells, thymocytes, and some

myeloid Myeloid tissue, in the bone marrow sense of the word '' myeloid'' ('' myelo-'' + '' -oid''), is tissue of bone marrow, of bone marrow cell lineage, or resembling bone marrow, and myelogenous tissue (''myelo-'' + '' -genous'') is any tissue ...

lineage cells (e.g.

macrophage Macrophages (; abbreviated MPhi, φ, MΦ or MP) are a type of white blood cell of the innate immune system that engulf and digest pathogens, such as cancer cells, microbes, cellular debris and foreign substances, which do not have proteins that ...

dendritic cell A dendritic cell (DC) is an antigen-presenting cell (also known as an ''accessory cell'') of the mammalian immune system. A DC's main function is to process antigen material and present it on the cell surface to the T cells of the immune system ...

s). ''IL2RA'' has been used as a marker to identify CD4+FoxP3+

regulatory T cell The regulatory T cells (Tregs or Treg cells), formerly known as suppressor T cells, are a subpopulation of T cells that modulate the immune system, maintain immune tolerance, tolerance to self-antigens, and prevent autoimmune disease. Treg ...

s in mice. However, there are species differences as CD25 is constitutively expressed by a large proportion of resting

memory T cell Memory T cells are a subset of T lymphocytes that might have some of the same functions as memory B cells. Their lineage is unclear. Function Antigen-specific memory T cells specific to viruses or other microbial molecules can be found in both ...

s non-regulatory CD4 T cells in humans that are absent in mice. High expression of CD25 is also found on TCR activated conventional T cells (both CD8+ and CD4+ T lymphocytes), where it is considered to be a marker of T cell activation. Additionally, expression of the IL-2 receptor alpha subunit can be found in non-lymphoid tissues such as lungs (

alveolar macrophage An alveolar macrophage, pulmonary macrophage, (or dust cell, or dust eater) is a type of macrophage, a phagocytosis#Professional phagocytic cells, professional phagocyte, found in the airways and at the level of the pulmonary alveolus, alveoli in ...

s), liver (

Kupffer cell Kupffer cells, also known as stellate macrophages and Kupffer–Browicz cells, are specialized cells localized in the liver within the lumen of the liver sinusoids and are adhesive to their endothelial cells which make up the blood vessel walls. K ...

s) and skin (

Langerhans cell A Langerhans cell (LC) is a tissue-resident macrophage of the skin once thought to be a resident dendritic cell. These cells contain organelles called Birbeck granules. They are present in all layers of the epidermis and are most prominent in t ...

s). ''IL2RA'' protein can be expressed in many types of neoplastic cells, such as in most B-cell neoplasms, T-cell

lymphoma Lymphoma is a group of blood and lymph tumors that develop from lymphocytes (a type of white blood cell). The name typically refers to just the cancerous versions rather than all such tumours. Signs and symptoms may include enlarged lymph node ...

s, some acute nonlymphocytic

leukemias Leukemia ( also spelled leukaemia; pronounced ) is a group of blood cancers that usually begin in the bone marrow and produce high numbers of abnormal blood cells. These blood cells are not fully developed and are called ''blasts'' or '' le ...

, neuroblastomas,

mastocytosis Mastocytosis, a type of mast cell A mast cell (also known as a mastocyte or a labrocyte) is a resident cell of connective tissue that contains many granules rich in histamine and heparin. Specifically, it is a type of granulocyte derived from ...

, Waldenstrom macroglobuliaemia and tumor infiltrating lymphocytes.

Structure

Interleukin-2 receptor alpha chain is an integral-membrane protein, more precisely

type I transmembrane protein A single-pass membrane protein also known as single-spanning protein or bitopic protein is a transmembrane protein that spans the lipid bilayer only once. These proteins may constitute up to 50% of all transmembrane proteins, depending on the or ...

. This bitopic polypeptide is constructed by a sequence of 272

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 a ...

s and has a molecular mass of around 30.8 kDa. CD25 consists of three domains: extracellular (N-terminus), transmembrane (alpha-helix) and cytoplasmic (C-terminus). However, while extracellular part is able to function as a

binding site In biochemistry and molecular biology, a binding site is a region on a macromolecule such as a protein that binds to another molecule with specificity. The binding partner of the macromolecule is often referred to as a ligand. Ligands may includ ...

for

, short cytoplasmic domain lacks an ability to induce intracellular signalling and therefore needs to oligomerise with other IL-2 receptor subunits. The

(IL2) receptor alpha (''IL2RA'') and beta ('' IL2RB)'' chains, together with the common gamma chain (''

''), constitute the high-affinity IL-2 receptor complex (''K''d ~10−11M). Homodimeric alpha chains (''IL2RA'') result in low-affinity receptor (''K''d ~10−8M) with no signalling ability, while dimeric beta ('' IL2RB'') and gamma chains (''

'') produce a medium-affinity receptor (''K''d ~10−9M). Moreover, CD25 is an exclusive subunit that entirely binds IL-2, while CD132 binds the shared γc family cytokines ( IL-4, IL-7, IL-9, IL-15 and IL-21), and the CD122 subunit binds also IL-15. Soluble ''IL2RA'' has been isolated and determined to result from extracellular

proteolysis Proteolysis is the breakdown of proteins into smaller polypeptides or amino acids. Protein degradation is a major regulatory mechanism of gene expression and contributes substantially to shaping mammalian proteomes. Uncatalysed, the hydrolysis o ...

during activation of T lymphocytes. Also, alternately-spliced ''IL2RA'' mRNAs have been isolated, but the significance of each is currently unknown.

Signalling cascade of interleukin-2 Receptor

Interleukin-2 can interact with intermediate-affinity dimeric IL-2 receptor, which consists of beta ( CD122) and gamma (

CD132 The common gamma chain (γc) (or CD132), also known as interleukin-2 receptor subunit gamma or IL-2RG, is a cytokine receptor sub-unit that is common to the receptor complexes for at least six different interleukin receptors: interleukin-2 recept ...

) chains or with high-affinity trimeric complex, where also alpha subunit (CD25) constructs the IL-2 receptor and provides enhanced specific binding force. After activation of the receptor by its

ligand In coordination chemistry, a ligand is an ion or molecule with a functional group that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's el ...

, heterodimerisation of beta and gamma intracellular domains takes place. This coupling of subunits brings together

Janus kinase Janus kinase (JAK) is a family of intracellular, non-receptor tyrosine kinases that transduce cytokine-mediated signals via the JAK-STAT pathway. They were initially named "just another kinase" 1 and 2 (since they were just two of many discoverie ...

s JAK1 and JAK3, considering their association with respective cytoplasmic parts of beta and gamma subunits. Downstream

phosphorylation In biochemistry, phosphorylation is described as the "transfer of a phosphate group" from a donor to an acceptor. A common phosphorylating agent (phosphate donor) is ATP and a common family of acceptor are alcohols: : This equation can be writ ...

leads to initiation of three signalling pathways: JAK-STAT pathway,

PI3K/Akt/mTOR pathway The PI3K/AKT/mTOR pathway is an intracellular signaling pathway important in regulating the cell cycle. Therefore, it is directly related to cellular quiescence, proliferation, cancer, and longevity. PI3K activation phosphorylates and activates ...

and Ras/Raf/MEK/ERK (MAPK) pathway. Regarding JAK-STAT pathway, particular signal transducers and activators of transcription participate in this signalling cascade: STAT5, STAT1 and

STAT3 Signal transducer and activator of transcription 3 (STAT3) is a transcription factor which in humans is encoded by the ''STAT3'' gene. It is a member of the STAT protein family. Function STAT3 is a member of the STAT protein family. In respon ...

and after dimerisation, they translocate to nucleus to perform

transcription factor In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription (genetics), transcription of genetics, genetic information from DNA to messenger RNA, by binding t ...

functions. All three signalling pathways are important for diverse cellular regulations, in terms of increased survival (anti- apoptotic effect), proliferation and

cell growth Cell most often refers to: * Cell (biology), the functional basic unit of life * Cellphone, a phone connected to a cellular network * Clandestine cell, a penetration-resistant form of a secret or outlawed organization * Electrochemical cell, a de ...

, transcriptional regulation and

cell differentiation Cellular differentiation is the process in which a stem cell changes from one type to a differentiated one. Usually, the cell changes to a more specialized type. Differentiation happens multiple times during the development of a multicellular ...

. T lymphocytes are influenced by IL-2R signalling in case of CD4+ T helper subtype differentiation: promoting Th1, Th2, Th9, Tfr (T follicular regulatory cells) and suppressing Th17, Tfh ( T follicular helper cells). Additionally, strength of IL-2R signalling in CD8+ T cytotoxic lymphocytes may be connected to phenotypic fate of these cells for effector and memory T cells formation.

Clinical significance

Roifman's group was the first to identify immunological consequences of CD25 loss and the patient has suffered from chronic infections and severe

autoimmunity In immunology, autoimmunity is the system of immune responses of an organism against its own healthy cells, tissues and other normal body constituents. Any disease resulting from this type of immune response is termed an " autoimmune disease ...

resembling Immune dysregulation, Polyendocrinopathy, Enteropathy X-linked ( IPEX) syndrome, caused by mutations in FOXP3 gene.

CD25 as a biomarker

Levels of CD25 soluble form, called ''sIL-2Rα'', has been connected to pathogenesis of

autoimmune disease An autoimmune disease is a condition that results from an anomalous response of the adaptive immune system, wherein it mistakenly targets and attacks healthy, functioning parts of the body as if they were foreign organisms. It is estimated tha ...

s and

cancer Cancer is a group of diseases involving Cell growth#Disorders, abnormal cell growth with the potential to Invasion (cancer), invade or Metastasis, spread to other parts of the body. These contrast with benign tumors, which do not spread. Po ...

. Since sCD25 is produced during immune activation, it is used as one of

biomarker In biomedical contexts, a biomarker, or biological marker, is a measurable indicator of some biological state or condition. Biomarkers are often measured and evaluated using blood, urine, or soft tissues to examine normal biological processes, ...

s to track disease progression and to indicate outcome for clinical disorders. Especially, it is a hallmark for hyper-activated immune system and cytokine storm, which may lead to multiple organ system failure. In cancer, increased levels of this soluble protein are diagnostic marker for

leukemia Leukemia ( also spelled leukaemia; pronounced ) is a group of blood cancers that usually begin in the bone marrow and produce high numbers of abnormal blood cells. These blood cells are not fully developed and are called ''blasts'' or '' ...

and

. Furthermore, ''sIL-2Rα'' levels have some significance also in

infectious diseases infection is the invasion of tissues by pathogens, their multiplication, and the reaction of host tissues to the infectious agent and the toxins they produce. An infectious disease, also known as a transmissible disease or communicable dise ...

and transplantation. Higher serum levels were correlated with severity and need for hospitalisation of

COVID-19 Coronavirus disease 2019 (COVID-19) is a contagious disease caused by the coronavirus SARS-CoV-2. In January 2020, the disease spread worldwide, resulting in the COVID-19 pandemic. The symptoms of COVID‑19 can vary but often include fever ...

patients. ''sIL-2Rα'' amount in plasma of HIV ( human immunodeficiency virus) positive patients has a correlation to HIV viral load and so to disease progression. Similarly in

Chagas disease Chagas disease, also known as American trypanosomiasis, is a tropical parasitic disease caused by ''Trypanosoma cruzi''. It is spread mostly by insects in the subfamily Triatominae, known as "kissing bugs". The symptoms change throughout the ...

, caused by the

protozoan Protozoa (: protozoan or protozoon; alternative plural: protozoans) are a polyphyletic group of single-celled eukaryotes, either free-living or parasitic, that feed on organic matter such as other microorganisms or organic debris. Historically ...

Trypanosoma cruzi ''Trypanosoma cruzi'' is a species of parasitic euglenoids. Among the protozoa, the trypanosomes characteristically bore tissue in another organism and feed on blood (primarily) and also lymph. This behaviour causes disease or the likelihood ...

,'' patients have increased levels of ''sIL-2Rα'' and

autoantibodies An autoantibody is an antibody (a type of protein) produced by the immune system that is directed against one or more of the individual's own proteins. Many autoimmune diseases (notably lupus erythematosus) are associated with such antibodies. Pr ...

. In regard to transplantation, higher levels of sCD25 may be used as a predictor of organ rejection and graft-versus-host disease (GVHD) for hematopoietic transplantations. Concerning CVD (cardiovascular diseases) soluble ''IL-2Rα'' has positive correlation with

hypertension Hypertension, also known as high blood pressure, is a Chronic condition, long-term Disease, medical condition in which the blood pressure in the artery, arteries is persistently elevated. High blood pressure usually does not cause symptoms i ...

, type 2 diabetes mellitus, cardiac sarcoidosis,

stroke Stroke is a medical condition in which poor cerebral circulation, blood flow to a part of the brain causes cell death. There are two main types of stroke: brain ischemia, ischemic, due to lack of blood flow, and intracranial hemorrhage, hemor ...

and

heart failure Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome caused by an impairment in the heart's ability to Cardiac cycle, fill with and pump blood. Although symptoms vary based on which side of the heart is affected, HF ...

. For neurological disorders, high levels of ''sIL-2Rα'' are a sign for increased risk of developing

schizophrenia Schizophrenia () is a mental disorder characterized variously by hallucinations (typically, Auditory hallucination#Schizophrenia, hearing voices), delusions, thought disorder, disorganized thinking and behavior, and Reduced affect display, f ...

CD25 as a therapeutic target

Since Tregs express ''IL-2Rα'' subunit constitutively on the surface, some immunotherapeutic approaches try to use this information for selectivity. NARA1

antibody An antibody (Ab) or immunoglobulin (Ig) is a large, Y-shaped protein belonging to the immunoglobulin superfamily which is used by the immune system to identify and neutralize antigens such as pathogenic bacteria, bacteria and viruses, includin ...

is used in antitumour approaches to preferentially supplement interleukin-2 to conventional CD8+ T cells . NARA1 binds to the cytokine on the ''IL-2Rα''

preventing binding to CD25. This complex should therefore interact with conventional T lymphocytes over T regulatory cells and thus increase

cytotoxic Cytotoxicity is the quality of being toxic to cells. Examples of toxic agents are toxic metals, toxic chemicals, microbe neurotoxins, radiation particles and even specific neurotransmitters when the system is out of balance. Also some types of dr ...

activity without increasing suppressing activity in tumour environment. Antibodies directly against CD25 have been altered to contain ‘activating’ Fc regions for the purpose of

antibody-dependent cell-mediated cytotoxicity Antibody-dependent cellular cytotoxicity (ADCC), also referred to as antibody-dependent cell-mediated cytotoxicity, is a mechanism of Cell-mediated immunity, cell-mediated immune defense whereby an effector cell of the immune system kills a target ...

, in this case Treg depletion. Antibody marks a cell with ''IL-2Rα'' subunit on the surface, which is subsequently recognized and cleared by

myeloid cell Myeloid tissue, in the bone marrow sense of the word ''wikt:myeloid#Adjective, myeloid'' (''wikt:myelo-#Prefix, myelo-'' + ''wikt:-oid#Suffix, -oid''), is tissue (biology), tissue of bone marrow, of bone marrow cell lineage, or resembling bon ...

with Fc receptor. Moreover, for treatment of

, drug called daclizumab binds to ''IL2RA'' and so blocks high-affinity IL-2 receptors on recently activated T cells for interaction with IL-2 as well as IL-2

cross-presentation Cross-presentation is the ability of certain professional antigen-presenting cells (mostly dendritic cells) to take up, process and present ''extracellular'' antigens with MHC class I molecules to CD8 T cells (cytotoxic T cells). Cross-priming, th ...

s. From the other side, treatment strategies for

autoimmune In immunology, autoimmunity is the system of immune responses of an organism against its own healthy cells, tissues and other normal body constituents. Any disease resulting from this type of immune response is termed an " autoimmune disease" ...

and inflammatory diseases need selectivity for Tregs and suppression of immune system. ''IL-2Rα'' subunit expression on Tregs secures better sensitivity to

IL-2 The Ilyushin Il-2 (Russian language, Russian: Илью́шин Ил-2) is a Ground attack aircraft, ground-attack plane that was produced by the Soviet Union in large numbers during the World War II, Second World War. The word ''shturmovík'' (C ...

. Therefore, administration of low doses of the cytokine preferentially stimulates T regulatory cells over others. Low-dose IL-2 therapy is used for

graft-versus-host disease Graft-versus-host disease (GvHD) is a syndrome, characterized by inflammation in different organs. GvHD is commonly associated with bone marrow transplants and stem cell transplants. White blood cells of the donor's immune system which rema ...

, type 1 diabetes mellitus,

hepatitis C Hepatitis C is an infectious disease caused by the hepatitis C virus (HCV) that primarily affects the liver; it is a type of viral hepatitis. During the initial infection period, people often have mild or no symptoms. Early symptoms can include ...

virus-induced

vasculitis Vasculitis is a group of disorders that destroy blood vessels by inflammation. Both artery, arteries and veins are affected. Lymphangitis (inflammation of lymphatic vessels) is sometimes considered a type of vasculitis. Vasculitis is primarily c ...

and systemic lupus.

References

External links

Mouse CD Antigen Chart

CD4+FoxP3+ regulatory T cells gradually accumulate in gliomas during tumor growth and efficiently suppress antiglioma immune responses in vivo
* {{Interleukin receptor modulators Clusters of differentiation